Studies in HIV-infected infants suggest that the insulin-like growth factor(IGF) axis may play a major role in the growth restriction and failure-to-thrive characteristic of disease. Although few studies have assessed the role of IGF in HIV-infected children, prior studies with the fetal monkey have shown that direct inoculation of the rhesus fetus with a cell-free uncloned pathogenic strain of SIV (SIVmac251) during the early second trimester results in severe intrauterine growth restriction (IUGR) and a disruption in the IGF axis. Here, IGF-I was found to be significantly diminished, whereas elevations in immunoreactive levels of IGF binding protein (IGFBP-3) were noted. We are currently investigating the mechanism(s) involved in these changes by assessing the role of cytokines (tumor necrosis factor, interleukins), nitric oxide synthase expression, and supplementation of the SIV-infected fetal monkey with IGF-I. Fetuses are directly inoculated with SIV via ultrasound-guidance during the early second trimester (gestational day [GD] 65), and growth and fetal hemodynamics sonographically assessed weekly during the course of gestation. Maternal and fetal blood samples are collected periodically to assess fetal immune response, virus, cytokine profiles, hematology, and serum biochemistry as clinical indicators of fetal compromise up to GD 130-140 (third trimester). Infants are delivered at term for postnatal studies. Although results are preliminary, studies indicate that fetuses supplemented with IGF-I show growth patterns within the normal range when compared to nontreated, SIV-infected fetuses. These studies will provide novel information on the utility of IGF-I supplementation for improving growth rates in the SIV-infected fetus, and address questions related to the mechanism(s) for the growth failure associated with disease. *KEY*SIV, Fetal growth, IGF-I, Growth restriction, Fetal therapy